WO1998007427A1 - Ligands liant des recepteurs de cocaine - Google Patents

Ligands liant des recepteurs de cocaine Download PDF

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Publication number
WO1998007427A1
WO1998007427A1 PCT/US1997/014702 US9714702W WO9807427A1 WO 1998007427 A1 WO1998007427 A1 WO 1998007427A1 US 9714702 W US9714702 W US 9714702W WO 9807427 A1 WO9807427 A1 WO 9807427A1
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Prior art keywords
alkyl
compound
rti
conh
nhcor
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PCT/US1997/014702
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English (en)
Inventor
Michael J. Kuhar
Frank I. Carroll
John W. Boja
Anita H. Lewin
Philip Abraham
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Research Triangle Institute
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Publication date
Priority claimed from US08/706,263 external-priority patent/US6531483B1/en
Application filed by Research Triangle Institute filed Critical Research Triangle Institute
Priority to EP97940580A priority Critical patent/EP0993301B1/fr
Priority to CA002263961A priority patent/CA2263961C/fr
Priority to DE69720800T priority patent/DE69720800T2/de
Priority to AT97940580T priority patent/ATE236635T1/de
Priority to AU42327/97A priority patent/AU4232797A/en
Priority to JP51095598A priority patent/JP4354531B2/ja
Publication of WO1998007427A1 publication Critical patent/WO1998007427A1/fr
Priority to AU83629/01A priority patent/AU778629B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • This invention is directed to a class of binding iigands for cocaine receptors and other receptors in the brain.
  • a novel family of compounds shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind to these receptors, for biochemical assays and imaging techniques. Such imaging is useful for determining effective doses of new drug candidates in human populations.
  • neurotransmitter receptors in the brain of the formula:
  • the iodo substituent may be at o, , p_, or multisubstituted
  • R 2 CH 3 , C 2 H S , CH 3 (CH 2 )j, (CH 3 ) 2 CH, C 6 H 5 , C 6 H 5 CH 2 , C 6 H 5 (CH 2 ) 2 ;
  • Sites of specific interest included cocaine receptors associated with dopamine (DA) transporter sites.
  • DA dopamine
  • R j may be an alkyl of 1-7 carbon atoms
  • CH 2 CR 3 CR ⁇ R S
  • the PCT filing also reveals the affinity cf r.ese compounds for cocaine receptors associated with serotonin ( 5-hydroxytryptamine, 5-HT) transporters, and confirms, for the first time, that the in vi tro binding reported in the earlier- filed application, is confirmed in in vivo testing.
  • affinity cf r.ese compounds for cocaine receptors associated with serotonin ( 5-hydroxytryptamine, 5-HT) transporters confirms, for the first time, that the in vi tro binding reported in the earlier- filed application, is confirmed in in vivo testing.
  • Specific disclosure for a variety of applications, including using the compounds in both PET and SPECT scanning, wherein either the iodine substituent, or one of the carbon groups is radioactive '1-123, 125 or 131 and Cll) thus providing methods for scanning for the presence of specific cocaine receptors.
  • Such scanning processes may be used to determine physiological conditions associated with dopamine and serotonin reuptabe inhibitors, which lead to behavioral and neurodegenerative
  • Such disorders include depression, bipolar disorder, eating disorders, obesity, attention deficit disorder, panic attacks and disorders, obsessive-compulsive disorder, Parkinson's Disease, and cocaine, nicotine and alcohol addiction.
  • These compounds in addition to being used in treatment of these disorders, may be used to examine in general the density and distribution of specific cocaine receptors n various parts of the brain and/or body, to determine the efficacy of neurological treatments aimed at halting or reversing the degeneration of specific nerves m the brain, and for screening drugs, such as antidepressant drugs.
  • Y is — C-O- R*, or
  • R is hydrogen, C,. 5 alkyl
  • R is phenyl, C t . 6 alkyl, C, ⁇ alkyl-substituted phenyl
  • R is C,. 6 alkyl, phenyl, C, ⁇ alkyl substituted phenyl and
  • Z is phenyl or naphtyi bearing 1-3 substituents selected from the group consisting of F, Cl, I, and alkyl.
  • These compounds exhibit unusually high affinity and specificity for binding to receptors for the dopamine transporter site, as well as the serotonin transporter site, based on inhibition of [ 3 H] paroxetine binding. This high affinity makes certain of these compounds particularly well suited for use as therapeutic agents, as well as for imaging agents for dopamine and serotonin transporters.
  • one object of this invention is to provide novel compounds which bind to cocaine receptors.
  • Another object of the invention is to provide novel 3- (substituted phenyl) -2- (substituted) tropane analogs which bind to cocaine receptors .
  • Still another object of the invention is to provide 3- (substituted phenyl) - 2 - (substituted) tropane analogs which bind preferentially to the dopamine transporter.
  • Yet- another object of the invention is to provide 3- (substituted phenyl) -2- (substituted) tropane analogs which bind preferentially to the serotonin transporter.
  • Another object of the invention is to provide a compound of the formula
  • R is CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 , R, is CH 3 , CH 2 C 6 H 5 , (CH 2 ) 2 C 6 H 5 , (CH 2 ) 3 C 6 H 5 , or
  • Another object of the invention is to provide compounds having the following formulas:
  • R hydrogen, C,. 5 alkyl
  • X H, C,. 6 alkyl, C 3 . 8 cycloalkyl, C alkoxy, C j . 6 alkynyl, halogen, amino, acylamido, and
  • R b is C,. 6 alkyl, phenyl, C,. 6 alkyl substituted phenyl be
  • a further object of the invention is to provide a method for treating psychostimulant abuse, by administering to a patient in need of such treatment a
  • a still further object of the invention is to provide method for inhibiting the action of a psychostimulant, by administering to a patient in need of such treatment
  • Still another object of the invention is to provide a method for inhibiting neurotransmitter re-uptake by administering to a patient in need of such treatment a neurotransmitter transporter-inhibiting amount of a 3-(substituted phenyl)-2- (substituted) tropane analog.
  • Another object of the invention is to provide a method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3- (substituted phenyl) -2- (substituted) tropane analog.
  • Still another object of the invention s to provide a method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3- (substituted phenyl) -2- (substituted) tropane analog.
  • the invention pertains to the discovery that certain cocaine analogs are particularly well suited for therapeutic use as neurochemical agents. These particular cocaine analogs, in modulating neurotransmitter actions, may also be useful for modulating the actions of pyschostimulant drugs, for modulating endocrine function, for modulating motor function, and for modulating complex behaviors.
  • Figure 1 depicts the scheme for convening 3 -(substituted phenyl)-2-tropane carboxyhc acid (tropane acid) to 2-subst ⁇ ruted tetrazoles.
  • oxazoies oxadiazoles, thiazoles, thiadiazoles and benzothiazole
  • Figure 2 depicts the scheme m which the carboxamide obtained from the tropane acid was treated to obtain rut ⁇ les and tetrazoles
  • Figure 3 depicts die scheme used to prepare 3-subst ⁇ tuted isoxazoles DETAILED DESCRIPTION OF THE INVENTION
  • the present invention includes novel compounds having the tollow g formula
  • the tropane acid was refiuxed w th N-acetyl and benzoic hydrazide m phosphorous oxychloride to obtain the corresponding 5 -substituted 1, 3 , 4 -oxadiazoles (Afanasiadi et al . , Chem. Heterocyclic Co pd. 397-400 (1995) ) .
  • N-benzoyl hydrazide amide obtained by the reaction cf the acid cnloride of tropane acid with N-benzo c hydrazide was cyclized with Lawesson's reagent (El-Barbary et al .
  • Figure 3 outlines the route used to prepare 3 -substituted isoxazole.
  • the known tropane compounds (Carroll et al., J. Med. Chem. 34:2719-2725 (1991)) were treated with dilithiated methyl or phenyl acetoneoximes, obtained by the treatment of acetone or acetophenoneoxime with n-BuLi at 0°C.
  • the corresponding addition product was cyclized without isolation using sulfuric acid at reflux temperature to furnish the recruired isoxazoles (Saunders et al. , 1990) .
  • both in vi tro and in vivo assay systems may be used for the screening of potential drugs which act as agonists or antagonists at cocaine receptors, or drugs which are effective to modulate neurotransmitter level or activity, in particular by binding to a transporter of that neurotransmitter .
  • any detectable moiety in particular a radioactive element
  • vi tro assays for binding are described in Boja et al Ann. NY Aca . Sci . 654:282-291 (1992), which is incorporated herein by reference in its entirety.
  • a particularly preferred in vi tro assay involves the ability of a compound in question to displace the binding of a known labelled compound to binding sites in a tissue sample, isolated membranes or synaptosomes .
  • the compounds may be analyzed by their ability to inhibit reuptake of a labelled neurotransmitter in a sample, in particular, in synaptosomes.
  • the compound or its binding partner (s) can also be labeled with any detectable moiety, but are preferably labelled with a radioactive element.
  • the radioactive label can be detected by any of the currently available counting procedures, including the imaging procedures detailed m the disclosures of the parent applications.
  • the preferred isotope may be selected from 3 H, C, 14 C, C, 32 P, 35 S, 36 C1, 51 Cr, 57 Co, 5 ⁇ Co, 59 Fe, 90 Y, l "i, *" ⁇ , and ⁇ a ⁇ Re.c,
  • the binding of the labelled compounds may be analyzed by various imaging techniques, including positron emission tomography (PET) , single photon emission computed tomography (SPECT) , autoradiogra , and the like.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • autoradiogra autoradiogra
  • imaging techniques are useful for determining effective doses of new drug candidates.
  • brain imaging studies By performing in vivo competition studies, it is possible to use brain imaging studies to determine the oral doses of new drug candidates, which produce significant receptor occupancy in the brain.
  • In vivo displacement studies which determine in vivo ICSO's which in turn reflect doses that occupy receptors in vivo are described n Cline et al '(1992) Synapse 12:37-46).
  • the binding of the compounds of the invention may be at any location where a receptor for a particular psychostimulant is present, and more specifically, any location where a dopamine or serotonin transporter is present.
  • locations are in general any area comprising a part of the dopamine or serotonin pathway, in particular at synapses.
  • locations known to be associated with dopamine transport include the cerebral cortex, hypothalamus , substantia nigra, nucleus accumbens , arcuate nucleus, anterior periventricular nuclei, median eminence and amygdala.
  • locations known to be associated with serotonin include the striatum, cerebral cortex, hypothalamus, Raphe nuclei, pre-optic area and suprachiasmatic nucleus.
  • psychostimulant any compounds whose abuse is dependent upon mesolimbic and mesocortical dopaminergic pathways .
  • psychostimulant relates to cocaine.
  • the compounds of the invention may also be used to treat abuse of compounds not traditionally classified as “psychostimulants, " but which act at a dopamine or serotonin transporter.
  • abused compounds include ethanol and nicotine.
  • the compounds of the invention may be prepared in pharmaceutical compositions, with a suitable carrier and at a strength effective for administration by various means to a patient experiencing an adverse medical condition associated with cocaine receptor binding or neurotransmitter release and reuptake, for the treatment thereof.
  • the action of the compounds may be analyzed by the imaging methods noted above, and also by behavioral studies.
  • the pharmaceutical effects of the compounds of the invention may be reflected in locomotor activity, including the induction of ipsilateral rotation, stereotyped sniffing and the "swim test" , in schedule-controlled operant behavior (i.e., response for food or shock termination) or drug self -administration. In general, maximal behavioral effects are seen at near complete occupancy of transporter sites.
  • a variety of administrative techniques may be utilized, among them oral or parenteral techniques such as subcutaneous, intravenous, intraperitoneal, intracerebral and intracerebroventricular injections, catheterizations and the like. Average quantities of the compounds may vary in accordance with the binding properties of the compound (i.e., affinity, onset and duration of binding) and in particular should be based upon the recommendations and prescription of a qualified physician or veterinarian.
  • the compounds of the invention preferably have a long duration of action, which is important to facilitate dosing schedules.
  • the present compounds In rats, the present compounds have a 7-10 fold longer duration of action than cocaine (Fleckenstein et al, "Highly potent cocaine analogs cause long- lasting increases in locomotor activity," Eur. J. Pharmacol . , in press, which is incorporated herein by reference in its entirety) .
  • the present compounds also preferably have a slow rate of entry into the brain, which is important in decreasing the potential for abuse ⁇ Stathis et al, supra, which is incorporated herein by reference in its entirety) .
  • the present, compounds enter the brain more slowly than cocaine.
  • compositions useful in practicing the therapeutic methods of this invention may include, in admixture, a pharmaceutically acceptable excipient (carrier) and one or more of the compounds of the invention, as described herein as an active ingredient.
  • compositions which contain such neuroactive compounds as active ingredients are well understood in the art.
  • Such compositions may be prepared for oral adminstration, or as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared.
  • the preparation can also be emulsified.
  • the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof.
  • the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, and pH buffering agents which enhance the effectiveness of the active ingredient.
  • the compounds of the invention can be formulated into the therapeutic composition as neutralized pharmaceutically acceptable salt forms.
  • unit dose when used in reference to a therapeutic composition of the present invention refers to physically discrete units suitable as unitary dosage for humans, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle.
  • compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • quantity to be administered depends on the subject to be treated, the presence of other agonists and antagonises in the subject's system, and degree of binding or inhibition of binding desired.
  • Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual.
  • suitable dosages may range from about 0.01 to about 1000, preferably about .25 to about 500, and more preferably 10 to 50 milligrams of active ingredient per kilogram body weight of individual per day and depend on the route of administration.
  • the exact dosage must be determined by factoring m rate of degradation in the stomach, absorption from the stomach, other medications administered, etc.
  • the compounds of the present invention may be administered for their activities as surrogate agonist medications for cocaine, nicotine, alcohol, amphetamine and other psychostimulant abuse. Because of their favorable binding characteristics to transporters of neurotransmitters , they may be used for inhibiting the uptake of dopamine, norepmephnne , serotonin and other monoamines.
  • the compounds of the present invention may find use as an ipsychotics , antidepressants , local anesthetics, anti-Parkinsonian agents, anti-obesity drugs, drugs useful in the treatment of bipolar disorder, eating disorders, obesity, attention deficit disorder, panic attacks and disorder, obsessive-compulsive disorder, sexual dysfunction, as anticholinergic agents and as sigma receptor drugs.
  • the compounds of the invention may also be useful in trea t ing neurodegenerative disorders, in particular for treating Parkinson's Disease, but also may be useful in the treatment of cocaine, nicotine and alcohol addiction.
  • the preferred compounds of the present invention are derived from the series of compounds designated RTI-4229. The physical properties of some of these compounds are given in Table I.
  • R s hydrogen, C s alkyl
  • R 2 hydrogen, C,. 6 alkyl, C 3 . 8 cycloalkyl, C alkoxy, C ⁇ alkynyl,
  • R 3 OH, hydrogen, C,. 6 alkyl, C 3 . 8 cycloalkyl, C M alkoxy, Cl, Br,
  • X H, C, ⁇ alkyl, C 3 _ 8 cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino, acylamido, C 2 H 5 , CH 2 CH 3 CH 3 , CH(CH 3 ) 2 ,
  • Z H, I, Br, Cl, F, CN, CF 3 , N0 2 , N 3 , OR x , CONH 2 , C0 2 R,, C,. 6 alkyl,
  • R 4 -R « are each C ⁇ alkyl
  • R and R ⁇ are independently H, C ⁇ 6 alkyl, C 1-6 alkene, C 1-6 aikyne, phenyl, phenyl substituted with 1-3 of C l-6 alkyl, alkene, alkyl or alkoxy, C l- ⁇ alkoxy, phenoxy, amine, amine substituted with 1-2 of C 1-6 alkyl, alkene, aikyne, alkoxy or phenyl or phenoxy or R and R 1 may combine to form heterocyclic structure including pyrrolidinyl, piperidinyl and morpholino moieties, unsubstituted or substituted with 1-2 C l- ⁇ alkyl, alkene, aikyne or alkoxy groups.
  • RTI-4229 series include the following: RTI-4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105,
  • DA dopamine
  • 5-HT 5-hydroxytryptamme (serotonin)
  • NE norepinephrine
  • DA [ 3 H]WIN 35,428
  • 5-HT [ 3 H] paroxetine
  • NE N [ 3 H] nisofetine:
  • Particularly preferred compounds include RTI -4229-77, 87, 113, 114, 117, 119, 120, 124, 125, 126, 130, 141, 143, 144, 151, 152, 154, 165, 171, 173, 176, 177, 180, 181, 194, 202, 295, 298, 319, 334, 335, 336, 337, 338. 345, 346, 347, 348, 352 and 353.
  • the chemical structures of these compounds are given below:
  • Particularly preferred compounds include RTI-4229-77, 87, 113, 1 14, 1 17, 119, 120, 124, 125, 126, 130, 141 , 143, 144, 151, 152, 154, 165, 171 , 173, 176, 177, 180, 181 , 194, 202, 295, 298, 319, 334, 335, 336, 337, 338, 345, 346, 347,
  • compound RTI-353 is a highly potent compound at the serotonin site, and is selective relative to the dopamine and norepinephrine sites. This compound is particularly useful as an antidepressan , and as an imaging agent for serotonin transporters.
  • Reaction products were purified by flash column chromatography using silica gel (mesh size 230-400) purchased from VWR Scientific. Thin layer chromatography (TLC) was performed on Whatman 254 nm fluorescent silica gel 60A (1 x 3 inches, 250 [ ⁇ L thickness]) precoated TLC plates using the solvent systems indicated. Developed chromatograms were evaluated under 254 nm UV light or with iodine.
  • the isoxazole was crystallized as the hydrochloride salt:

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Abstract

L'invention concerne de nouveaux composés qui manifestent une forte affinité pour des récepteurs de cocaïne dans le cerveau, en particulier des sites transporteurs de dopamine et de sérotonine. Lesdits composés peuvent être utilisés comme agents de formation d'images ou comme agents thérapeutiques ainsi que dans le diagnostic et le traitement de la toxicomanie, de la dépression, de l'anorexie et de maladies neurodégénératives.
PCT/US1997/014702 1996-08-22 1997-08-22 Ligands liant des recepteurs de cocaine WO1998007427A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP97940580A EP0993301B1 (fr) 1996-08-22 1997-08-22 Ligands liant des recepteurs de cocaine
CA002263961A CA2263961C (fr) 1996-08-22 1997-08-22 Ligands liant des recepteurs de cocaine
DE69720800T DE69720800T2 (de) 1996-08-22 1997-08-22 Cocain-rezeptor bindende liganden
AT97940580T ATE236635T1 (de) 1996-08-22 1997-08-22 Cocain-rezeptor bindende liganden
AU42327/97A AU4232797A (en) 1996-08-22 1997-08-22 Cocaine receptor binding ligands
JP51095598A JP4354531B2 (ja) 1996-08-22 1997-08-22 コカイン受容体結合性リガンド
AU83629/01A AU778629B2 (en) 1996-08-22 2001-10-25 Cocaine receptor binding ligands

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US70150396A 1996-08-22 1996-08-22
US08/701,503 1996-08-22
US08/706,263 1996-09-04
US08/706,263 US6531483B1 (en) 1990-08-09 1996-09-04 Cocaine receptor binding ligands
US08/823,563 US5935953A (en) 1990-08-09 1997-03-25 Methods for controlling invertebrate pests using cocaine receptor binding ligands
US08/823,563 1997-03-25

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EP (1) EP0993301B1 (fr)
JP (2) JP4354531B2 (fr)
AT (1) ATE236635T1 (fr)
AU (1) AU4232797A (fr)
CA (1) CA2263961C (fr)
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* Cited by examiner, † Cited by third party
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EP0944626A1 (fr) * 1996-12-02 1999-09-29 Georgetown University Derives tropane et procede de synthese
WO1999055703A1 (fr) * 1998-04-29 1999-11-04 Zeneca Limited 2-alkyl-3-(hetero)aryl-8-azabicyclo[3.2.1]alcanes utilises comme pesticides
EP1079833A1 (fr) * 1998-05-22 2001-03-07 Research Triangle Institute Ligands se fixant sur les recepteurs de cocaine
WO2002102801A1 (fr) * 2001-05-23 2002-12-27 Neurosearch A/S Derives du tropane et utilisation de ces derniers comme inhibiteurs de recaptage du neurotransmetteur monoamine
WO2003014114A2 (fr) * 2001-08-08 2003-02-20 Neurosearch A/S Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine

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US6900228B1 (en) 1998-03-10 2005-05-31 Research Triangle Institute Opiate compounds, methods of making and methods of use
US6150376A (en) * 1998-08-05 2000-11-21 Georgetown University Bi- and tri-cyclic aza compounds and their uses
US6538010B1 (en) * 2000-11-08 2003-03-25 Research Triangle Institute Compounds and methods for promoting smoking cessation
PT1731518E (pt) * 2004-03-31 2014-09-18 Nippon Soda Co Composto amina cíclico e agente de controlo de pragas
US7872023B2 (en) * 2005-02-17 2011-01-18 Research Triangle Institute Kappa opioid receptor ligands
US7399762B2 (en) * 2005-04-25 2008-07-15 Research Triangle Institute Opioid receptor agonist compounds and their use in treatment of pain
US7476679B2 (en) * 2005-07-26 2009-01-13 Research Triangle Institute Octahydroisoquinoline compounds as opioid receptor modulators
EA014057B1 (ru) * 2005-10-06 2010-08-30 Ниппон Сода Ко., Лтд. Поперечно связанные соединения циклических аминов и средства для борьбы с вредителями
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EP0944626A1 (fr) * 1996-12-02 1999-09-29 Georgetown University Derives tropane et procede de synthese
EP0944626A4 (fr) * 1996-12-02 2002-09-04 Univ Georgetown Derives tropane et procede de synthese
WO1999055703A1 (fr) * 1998-04-29 1999-11-04 Zeneca Limited 2-alkyl-3-(hetero)aryl-8-azabicyclo[3.2.1]alcanes utilises comme pesticides
EP1079833A1 (fr) * 1998-05-22 2001-03-07 Research Triangle Institute Ligands se fixant sur les recepteurs de cocaine
JP2002516278A (ja) * 1998-05-22 2002-06-04 リサーチ・トライアングル・インスティチュート コカイン受容体結合リガンド
EP1079833A4 (fr) * 1998-05-22 2002-12-18 Res Triangle Inst Ligands se fixant sur les recepteurs de cocaine
WO2002102801A1 (fr) * 2001-05-23 2002-12-27 Neurosearch A/S Derives du tropane et utilisation de ces derniers comme inhibiteurs de recaptage du neurotransmetteur monoamine
WO2003014114A2 (fr) * 2001-08-08 2003-02-20 Neurosearch A/S Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine
WO2003014114A3 (fr) * 2001-08-08 2004-03-04 Neurosearch As Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine

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EP0993301B1 (fr) 2003-04-09
AU4232797A (en) 1998-03-06
ATE236635T1 (de) 2003-04-15
DE69720800T2 (de) 2004-01-29
JP2009102364A (ja) 2009-05-14
US5935953A (en) 1999-08-10
EP0993301A1 (fr) 2000-04-19
EP0993301A4 (fr) 2000-04-19
CA2263961C (fr) 2007-03-06
JP2001525795A (ja) 2001-12-11
DE69720800D1 (de) 2003-05-15
JP4354531B2 (ja) 2009-10-28
CA2263961A1 (fr) 1998-02-26

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